The neurotransmitter acetylcholine (ACh) interacts with two types of receptors in effector cell membranes: nicotinic receptors (nAChR), which are ligand-gated ion channels, and muscarinic receptors (mAChR), which are G protein-coupled receptors. In mammals five subtypes of mAChR, designated M1 to M5, have been identified. The M1 muscarinic receptor (M1R) is found in both the central and peripheral nervous systems, particularly the cerebral cortex and sympathetic ganglia. The muscarinic effects mediated by M1R have been studied largely by use of M1R-selective antagonists and, more recently, by the development of M1R-null mice.
Although no currently known mAChR antagonists display absolute selectivity for a single muscarinic receptor subtype, the drugs pirenzepine and telenzepine exhibit high relative affinity for M1R and are therefore often considered M1R-selective. Pirenzepine is used to treat peptic ulcer disease in Europe, Japan and Canada. Telenzepine has been tested in clinical trials for the same indication. At therapeutic doses, they moderately reduce gastric acid and pepsin secretion without inhibiting smooth muscle activity as do non-selective mAChR antagonists.
There are several lines of evidence suggesting that the M1R subtype may be involved in certain aspects of depressive disorders and anxiety. Direct injection of pirenzepine into the nucleus accumbens in the forebrain of rats resulted in increased swimming time in the Porsolt swim test (see, Chau, D. T., et al., Neuroscience, 2001, vol. 104, no. 3, pp. 791-8), a common measure of antidepressant activity. M1R-null mice also displayed increased swimming time in the Porsolt swim test, as well as increased social contacts in a social interaction test (see, Miyakawa, T., et al., J. Neurosci., 2001, vol. 21, no. 14, pp. 5239-50).
While pirenzepine and telenzepine are structurally similar to tricyclic antidepressants such as imipramine, they are not known to have psychotropic effects when taken orally for the treatment of peptic ulcer disease. In addition, in earlier studies of mice and rats, pirenzepine administered systemically failed to elicit any behavioral effects (see, Rogoz, Z., Skuza, G., Sowinska, H., Pol. J. Pharmacol. Pharm., 1981, vol. 31, pp. 615-26). The lack of such effects can be explained by the observation that pirenzepine does not exhibit significant penetration of the blood-brain barrier in various species, including rodents and humans (see, Hammer, R., Koss, F. W., Scand. J. Gastroenterol., Suppl., 1979, vol. 14, no. 57, pp. 1-6; Bymaster, F. P., et al., J. Pharmacol. Exp. Ther., 1993, vol. 267, no. 1, pp. 16-24). It is for that reason that the above-mentioned study of the effect of pirenzepine in the Porsolt swim test utilized direct injection of the drug into the brain of test animals.
There exists a need for new and effective medications for the treatment of psychological conditions, including depression. The present invention addresses this and other needs.